Integrin α11 is overexpressed by tumour stroma of head and neck squamous cell carcinoma and correlates positively with alpha smooth muscle actin expression

Abstract

BackgroundCancer‐associated fibroblasts (CAFs) were shown to be important for tumour progression in head and neck squamous cell carcinomas (HNSCCs). Their heterogeneity and lack of specific markers is increasingly recognized. Integrin α11 was recently shown to be expressed by CAFs and might serve as a specific CAF marker.AimTo investigate integrin α11 expression and its correlation with the expression of a well‐known marker of CAF, alpha smooth muscle actin (α‐SMA), in HNSCC.MethodsFresh frozen (FF) and formalin‐fixed paraffin‐embedded (FFPE) samples from healthy volunteers (n = 24), oral lichen planus (OLP) (n = 32) and HNSCC (n = 106) were collected together with clinical data after ethical approval. Immunohistochemistry to detect integrin α11 and α‐SMA was performed on FF and FFPE samples. qPCR for integrin α11 (ITGA11) and α‐SMA (ACTA2) was performed on FF samples. Data were analysed using chi‐square test and Kaplan–Meier survival analysis.ResultsSignificantly higher levels of integrin α11 and α‐SMA at both protein and mRNA levels were found in HNSCC vs. normal controls and OLP. A strong correlation was found between integrin α11 and α‐SMA expression, and double staining showed their colocalization. Both integrin α11 and α‐SMA were detected surrounding metastatic islands. Expression of α‐SMA at tumour front but not tumour centre correlated with patient survival.ConclusionIntegrin α11 was overexpressed in HNSCC stroma and colocalized with α‐SMA. Expression of α‐SMA at tumour front but not tumour centre had prognostic value for survival, pinpointing the importance of assessing tumour front when evaluating stromal molecules as prognostic biomarkers.

Oral cancer‐associated fibroblasts predict poor survival: Systematic review and meta‐analysis

“…Out of these, we then excluded 48 case reports, 73 reviews/meta‐analyses, and 866 studies that examined the molecular and biological mechanisms of CAFs with no data on prognosis/survival/mortality of patients. After title/abstract screening, 20 text articles were subjected for full‐text evaluation, out of which nine were excluded for the following reasons: cases of OSCC not limited to the oral cavity (Parajuli et al, ), no Kaplan–Meier survival plots (Fonseca et al, ; Kellermann et al, , ; Lim et al, ; Vered, Dayan, et al, ; Zhou et al, ), immunohistochemical staining for the identification of CAFs other than α‐SMA (Inoue et al, ), and missing data (i.e., CAF density, mean age of patients and gender classification) (Inoue et al, ; Sobral et al, ). Finally, 11 articles were included in the meta‐analysis (Bae et al, ; Bello et al, ; Dayan et al, ; Dhanda et al, ; Ding et al, ; Fujii et al, ; Kawashiri et al, ; Li et al, ; Marsh et al, ; Matsuoka et al, ; Vered, Dobriyan, et al, ) (Table ; Figure ).…”

Prognostic value of the immunohistochemical detection of cancer‐associated fibroblasts in oral cancer: A systematic review and meta‐analysis

“…The selected studies were published between 2007 and 2017 and were all written in English. They were conducted in 8 different countries: Brazil, Japan, Israel, China, Finland, England, Croatia, and Norway . In addition, 2 studies were performed in collaboration, 1 between Finland and Israel and 1 between Brazil and Finland .…”

“…Based on the MAStARI assessment, 3 articles were classified as carrying a high risk of bias, mainly because the answers for questions 3 and 4 (related to confounding factors and outcomes, respectively) were “no”. Sixteen studies were classified as with moderate risk for bias and 1 study was classified as low risk of bias (Table ).…”

Myofibroblasts in oral potentially malignant disorders: Is it related to malignant transformation?

“…The only study conducted with AC (Bianco et al., ) showed positivity for myofibroblasts in all samples, regardless the intensity of dysplasia. For OLP, no myofibroblasts were found in the stroma of a cohort containing 32 samples (Parajuli et al., ).…”

“…Consistently, the inclusion only of the studies that applied the strict WHO diagnostic criteria of 2003, accounting to 3803 cases, revealed a transformation potential of 0.9%. Unfortunately, there is only one study evaluating myofibroblasts in OLP (Parajuli et al, 2017), and of 32 cases, none revealed α-SMA-positive myofibroblasts. This finding is not unexpected, as OLP is a common chronic inflammatory disease characterized by a disequilibrium in the expression patterns of various inflammation-related cytokines, including transforming growth factorβ (TGFβ) and interferonγ (IFNγ) (Lu, Zhang, Sun, Du, & Zhou, 2015)-master keys on myofibroblast activation (Sobral, Montan, Martelli-Junior, Graner, & Coletta, 2007).…”